Dehydroevodiamine Targeting ACHE and ALDH3A1 Regulate Glycolytic Metabolism to Inhibit Hepatocellular Carcinoma Cell Apoptosis

Abstract

Dehydroevodiamine (DHE), a natural quinazoline alkaloid used in Chinese herbal medicine, exhibits promising antitumor properties in various cancers, including gastric cancer. Glycolysis is essential for tumor proliferation and survival. The antitumor effect of DHE on hepatoma cells (hepatocellular carcinoma, HCC) and the mechanism underlying the glycolytic regulation remain unclear. In this study, the cell viability, apoptosis rate, lactate release, and glucose uptake were evaluated in hepatoma cells treated with DHE. Cell metabolites were analyzed using GC-MS, and network pharmacology was employed to identify potential drug targets for DHE. Furthermore, the antiproliferative effect of DHE on liver cancer cells was examined by silencing the identified drug target. DHE promotes the apoptosis of Huh-7 and PLC cells. Cell metabonomics studies have shown that DHE primarily modulates the glycolysis/gluconeogenesis pathway. Simultaneously, DHE can inhibit the key enzymes HK2, PFKFB3, and LDHA of the glycolysis pathway, thus inhibiting glucose uptake and lactic acid production. Network pharmacological analysis identified ACHE and ALDH3A1 as the drug targets of DHE in liver cancer. Silencing ACHE and ALDH3A1 resulted in the loss of the apoptosis-promoting effect of DHE. Thus, DHE sensitizes aerobic glycolytic hepatoma cells to apoptosis by directly downregulating ACHE and ALDH3A1, leading to the inactivation of HK2, PFKFB3, and LDHA and suppression of aerobic glycolysis. DHE effectively inhibits the progression of liver cancer, primarily by reducing glucose metabolism, thereby inhibiting apoptosis of liver cancer cells. Therefore, DHE could be a promising agent for molecular-targeted cancer treatment strategies.